title: Canonical Nlrp3 inflammasome links systemic low-grade inflammation to functional decline in aging.
abstract: Despite a wealth of clinical data showing an association between inflammation and degenerative disorders in the elderly, the immune sensors that causally link systemic inflammation to aging remain unclear. Here we detail a mechanism by which the Nlrp3 inflammasome controls systemic low-grade age-related "sterile" inflammation in both periphery and brain independently of the noncanonical caspase-11 inflammasome. Ablation of Nlrp3 inflammasome protected mice from age-related increases in the innate immune activation, alterations in CNS transcriptome, and astrogliosis. Consistent with the hypothesis that systemic low-grade inflammation promotes age-related degenerative changes, the deficient Nlrp3 inflammasome-mediated caspase-1 activity improved glycemic control and attenuated bone loss and thymic demise. Notably, IL-1 mediated only Nlrp3 inflammasome-dependent improvement in cognitive function and motor performance in aged mice. These studies reveal Nlrp3 inflammasome as an upstream target that controls age-related inflammation and offer an innovative therapeutic strategy to lower Nlrp3 activity to delay multiple age-related chronic diseases.
authors.affiliation: Pennington Biomedical Research Center, LSU System, Baton Rouge, LA 70808, USA.
authors.forename: Yun-Hee
authors.initials: YH
authors.lastname: Youm
authors.forename: Ryan W
authors.initials: RW
authors.lastname: Grant
authors.forename: Laura R
authors.initials: LR
authors.lastname: McCabe
authors.forename: Diana C
authors.initials: DC
authors.lastname: Albarado
authors.forename: Kim Yen
authors.initials: KY
authors.lastname: Nguyen
authors.forename: Anthony
authors.initials: A
authors.lastname: Ravussin
authors.forename: Paul
authors.initials: P
authors.lastname: Pistell
authors.forename: Susan
authors.initials: S
authors.lastname: Newman
authors.forename: Renee
authors.initials: R
authors.lastname: Carter
authors.forename: Amanda
authors.initials: A
authors.lastname: Laque
authors.forename: Heike
authors.initials: H
authors.lastname: Münzberg
authors.forename: Clifford J
authors.initials: CJ
authors.lastname: Rosen
authors.forename: Donald K
authors.initials: DK
authors.lastname: Ingram
authors.forename: J Michael
authors.initials: JM
authors.lastname: Salbaum
authors.forename: Vishwa Deep
authors.initials: VD
authors.lastname: Dixit
mesh_terms: D000375:Aging; D000818:Animals; D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D020170:Caspase 1 / Q000378:metabolism; D020169:Caspases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D053471:Caspases, Initiator; D003071:Cognition / Q000502:physiology; D003598:Cytoskeletal Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D018149:Glucose Intolerance; D006624:Hippocampus / Q000378:metabolism; D007113:Immunity, Innate; D058847:Inflammasomes / Q000378:metabolism*; D007375:Interleukin-1 / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity / Q000502:physiology; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D017472:Receptors, Interleukin-1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D059467:Transcriptome
chemical_list: D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D058847:Inflammasomes; D007375:Interleukin-1; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; C498534:Pycard protein, mouse; D017472:Receptors, Interleukin-1; C101136:Casp4 protein, mouse; D020169:Caspases; D053471:Caspases, Initiator; D020170:Caspase 1